Prostate specific antigen (PSA) is an androgen-regulated serine protease produced by secretory epithelial cells lining the lumen of normal prostatic glands and the majority of prostate cancers. Sensabaugh, Isolation and characterization of a semen-specific protein from human seminal plasma: A potential new marker for semen identification. J Forensic Sci 1978; 23:106; Sinha et al., Immunoelectron microscopic localization of prostate-specific antigen in human prostate by the protein A-gold complex. Cancer 1987; 60:1288-93; Stamey et al., Prostate-specific antigen as a serum marker for andenocarcinoma of the prostate. N Engl J Med 1987; 317:909-16. The prostate is the major source of PSA. Sensabaugh; Stamey et al.; Hara et al., Immunochemical characteristics of human specific component “γ-Sm”. Nippon Hoigaku Zasshi 1969; 23:333; Stamey et al., Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. Untreated patients. J Urology 1989; 141:1070-5. Because of the prostate specificity of PSA expression it has become the most widely used marker for prostate cancer screening and response to therapeutic intervention. Many clinicians consider a serum PSA concentration greater than 4 ng/ml to be abnormal and recommend further screening by needle biopsy upon such a finding. However, PSA testing has a low sensitivity and specificity for detecting prostate cancer. Factors that can contribute to this low sensitivity and specificity include the presence of any non-cancerous prostatic disease (i.e. prostatitis or benign prostatic hyperplasia), age, and race.
There are three androgen response elements that are defined in the PSA promoter. Androgen response element (ARE) I and ARE II are located in the proximal PSA promoter centered at −170 bp and −394 bp from the transcription start site respectively. Xue et al., Genetic determinants of serum prostate-specific antigen levels in healthy men from a multiethnic cohort. Cancer Epidemiol Biomark Prev 2001; 10:575-9. The androgen response element (ARE) I is a high affinity ARE in the PSA gene. Cleutjens et al., Two androgen response regions cooperate in steroid hormone regulated activity of the prostate-specific antigen promoter. J Biol Chem 1996; 271:6379-88. Recently, genetic polymorphism in ARE I has been reported to be associated with PSA levels. Xue et al., Cancer Epidemiol Biomark Prev 2001. This polymorphism is a G/A change at position −158 in the PSA gene, with approximately 50:50 ratios for the two alleles in Caucasians. Rao et al., Identification of a polymorphism in the ARE I region of the PSA promoter. Proc Amer Assn Cancer Res 1999; 40:60. It was demonstrated that an association of the A allele occurs with increased serum PSA in healthy men. Cleutjens et al. This polymorphism has also been associated with increased risk for the development of prostate cancer. Xue et al., Susceptibility to prostate cancer: interaction between genotypes at the androgen receptor and prostate-specific antigen loci. Cancer Res 2000; 60:839-41; Medieros et al., Linkage between polymorphisms in the prostate specific antigen AREI gene region, prostate cancer risk, and circulating tumor cells. Prostate 2002; 53:88-94. Recent studies evaluated the association of this polymorphism with serum PSA in two separate study groups of men without prostate cancer and found no associations. Xu et al., Association studies of serum prostate-specific antigen levels and the genetic polymorphisms at the androgen receptor and prostate-specific antigen genes. Cancer Epidemiol Biomarkers Prev 2002; 11:664-9; Rao et al., Analysis of the G/A polymorphism in the androgen response element I of the PSA gene and its interactions with the androgen receptor polymorphisms. Urology 2002; 61:864-69.
ARE III is located in the 5′ upstream enhancer region centered at −4200. Cleutjens et al., An androgen response element in a far upstream enhancer region is essential for high, androgen-regulated activity of the prostate-specific antigen promoter. Molec Endocrinol 1997; 11:148-61; Schuur et al., Prostate-specific antigen expression is regulated by an upstream enhancer. J Biol Chem 1996:7043-51; ARE I and ARE III have been shown to have a high affinity for the androgen receptor, while ARE II is a low affinity ARE; Xue et al., Cancer Epidemiol Biomark Prev 2001; Huang et al., Cooperative assembly of androgen receptor into a nucleoprotein complex that regulates the prostate-specific antigen enhancer. J Biol Chem 1999; 274:25756-68; Schuur et al., Prostate-specific antigen expression is regulated by an upstream enhancer. J Biol Chem 1996:7043-51; Pang et al., Prostate tissue specificity of the prostate-specific antigen promoter isolated from a patient with prostate cancer. Hum Gene Therapy 1995; 6:1417-26; Zhang et al., Defining a functional androgen responsive element in the 5′ far upstream flanking region of the prostate-specific antigen gene. Biochem Biophys Res Comm 1997; 231:784-8; and Zhang et al., Identification of two novel cis-elements in the promoter of the prostate-specific antigen gene that are required to enhance androgen receptor-mediated transactivation. Nucleic Acids Res 1997; 25:3143-50. Recent data demonstrates the presence of multiple high, medium, and low affinity AREs located in the upstream enhancer region between −3870 and −4366 of the PSA promoter. Huang et al. Few reports have evaluated the contributions of sequences 5′ to −5322 of the PSA gene. This is due largely to the presence of a unique Xba I restriction site at this location that is useful for cloning promoter constructs. Thus, it could be beneficial to locate previously unrecognized functional region of the PSA gene that contains polymorphisms with a significant impact on serum PSA in healthy men.